An immunohistochemical study of p53 and PCNA in
inflammatory papillary hyperplasia of the palate: a
dilemma of interpretation
I Kaplan, M Vered, D Moskona, A Buchner, D Dayan
Department of Oral Pathology and Oral Medicine, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv
Universify, Tel Aviv, Israel
OBJECTIVE Inflammatory papillary hyperplasia of the
palate (IPHP) or the granular type of denture stomatitis,
is a non-neoplastic lesion characterized histologically by
a significant epithelial hyperplasia and inflammatory
infiltrate usually caused by trauma and Candida infection.
p53 and proliferative cell nuclear antigen (PCNA) are
cell-cycle regulators, that when overexpressed, are con-
sidered by many investigators as markers of malignant
transformation. The objective of this study was t o investi-
gate the immunodetection of p53 and PCNA in IPHP,
and t o correlate these results with the degree of epi-
thelial hyperplasia and inflammatory infiltrate.
MATERIALS AND METHODS In I 2 cases diagnosed
clinically as IPHP, Candida was cultured from the denture
base and the palatal rnucosa Lesions were biopsied and
stained with H&E for histomorphometric analysis of the
epithelial width and inflammatory infiltrate. PAS and
Gram stains were used for screening of Candida. Sections
were imrnunostained with DO-7 for p53 and PC-I0 for
PCNA. Fifteen palatal biopsies obtained from autopsies
of edentulous subjects with normal palatal mucosa
served as controls.
RESULTS: All cultures of swabs from both the palatal
mucosa and denture base were positive for Candida. Can-
didal hyphae could not be identified in PAS stained sec-
tions. Small foci o f Gram-positive organisms were found
in two cases of IPHP. Epithelial width and inflammation
were significantly higher in IPHP than in controls
(P < 0.001). A three-fold increase in positively stained
cells for p53 and a two-fold increase in positively stained
cells for PCNA were seen in IPHP compared with con-
trols (P < 0.00 I).
CONCLUSION: Although a significant increase in the
immunodetection of p53 and PCNA may indicate a
malignant potential, IPHP has never been reported t o
undergo malignant transformation nor is it associated
with cytologic signs of dysplasia. The increase in the epi-
thelial width and inflammation degree is probably asso-
Correspondence: Dr Dan Dayan. Depanrnent of On1 Pathology and On1
Medicine, School of Dental Medicine, TeI Aviv University, Tel Aviv.
Isnel. Fax: 00 977 3 6409 750
Received 12 May 1997; revised 22 J a n u q and 17 March 1998; accepted
17 Mnrch 1998
ciated with the colonization of the denture bases with
Candida organisms. The increased detection of p53 and
PCNA can be a secondary effect of cytokines originating
from both the inflammatory cells and the keratinocytes.
Thus, immunodetection of p53 and PCNA by current
immunohistochemical methods on archival tissues is
neither specific nor sensitive enough t o be used as indi-
cators for malignant potential in the absence of cytolog-
ical dysplastic changes o r genetic proof of mutated cell
cycle genes.
Keywords: p53; PCNA; immunohistochemisuy; papillary
hyperplasia; Candida
Introduction
Inflammatory papillary hyperplasia of the palate (IPHP) or
the granular type of denture stomatitis (Newton, 1962;
Budtz-J~rgensen, 1970) is a reactive tissue overgrowth.
characterized by a hyperemic mucosa with nodular or papil-
lary appearance, mostly covering the central part of the pal-
ate (Neville er 01, 1995). Although the exact pathogenesis
is still unclear, a combination of trauma and Candidu infec-
tion have been suggested as etiologic factors (Budtz-
Jorgensen and Bertram, 1970a, b; Ettinger, 1975; Bergendal
and Isacsson. 1983).
IPHP is related to ill-fitting dentures, poor denture
hygiene and wearing dentures 24-h a day. Its frequency in
denture-wearing elderly patients is between 5-20% (Budtz-
Jorgensen. 1975; Ettinger, 1975; Kaplan and Moskona.
1990; Moskona and Kaplan, 1992; Neville et al, 1995). Old
dentures are associated more frequently with IPHP than
newer ones, independent of denture quality (Kaplan and
Moskona, 1990; Moskona and Kaplan, 1992). This has
been attributed to surface changes, such as increased
porosity, which probably occurs with time in an acrylic
base denture, thus facilitating adhesion and colonization by
Cundida (Catalan et al, 1987; Segal et al, 1988, 1992).
The microscopic picture of IPHP exhibits papillary pro-
jections covered by keratinized stratified squamous epi-
thelium. The deepest aspects of the epithelium may show
pseudoepitheliomatous hyperplasia. The connective tissue
core beneath the epithelium varies from loose and edemat-

ous to densely collapsnized and is usually infiltrated by
chronic inflammato? cells. consisting mainly of lympho-
cytes and p l a m a cells t Budtz-Jorgensen. 1970; Bergend21
and lsachson. 1 9 3 : h'eville er al. 1995 t.
p53 and proliferatiie cell nuclear antigen ( P C S A ) are
cell-cycle replators. that when uLerexpressed. are cun-
sidered by man! in\estigators as markers of malignant
transformation. Immunohiqtochemistr! is the most widely
used method to detect these markers in studies of human
specimens (Johnson er a!. 1993: Sidransky. 1997).
The purpo3e of the prebent study was to investigdte
immunodetection of p53 and PCNA in the inflammatory.
non-neoplastic lesion IPHP. and to correlate these results
with the degree of epithelial hyperplasia and inflamrna-
tory infiltrate.
Materials and methods
From the file5 of the Geriatric Dental Clinic. School of
Dental h!edicine, Tel Abiv Universit?. from 1991 through
1995. 12 cases of clinically diagnosed IPHP in denture-
wearing patients (eight females. four males) were retrieved.
Age ranged from 46 to 79 years (mean 68 years). The con-
trol group consisted of 15 palatal specimens talien from
edentulous subjects with normal appearing palatal mucosa.
These were obtained from autopsies performed at the For-
ensic Pathology Institute in Tel AviL and consisted of eight
females and seven males. Age ranged from 62 to 90 years
(mean 72 years).
Samples lor microbiologic examination bere obtained b!
rubbing a sterile cotton-tipped swab m e r the lesions on the
palate and oier the denture base. Swabs were then gently
rubbed on Sabouraud's agar glucose containing penicillin
and streptom>cin. The samples uere cultured for I week
at room temperature (Silverman er al. 1990).
Lision biopsies were performed and submitted for his-
Ex-' '
lopathologic examination. The tissue specimens were fined
in 10% buffered formalin for a maximum of 23 h. followed
bq paraftin embecldinp. Autopsy specimens underwent the
same procedures.
From each block. 5 p m thick section5 were cut and rou-
tinelq stained with Hematoxylin and Eosin (H&E,. PAS
and Gram. All PAS and Gram-stained slides were screened
for the prswncc et' Cmtliih h>phae or pseudo-hyphae and
bacterial colonies at a magnification of ~100.
ltnmirn(~hisroc~liertii~
Sections. 3 p m thick. were mounted on silane-coated slide5
for immunohistochemical stains with DO-7 (Dako.
Denmark) for p5-3 and PC- 10 (Dako. Denmark) for PCNA.
Procedures used for immunostaining were the avidin-biotin
methods and microwave heating for antigen retrieval (for
p53 only).
p53 staining
Sections were dried at 37°C for 1 h, dewaxed at 60°C for
I h. placed in x).lol for 30 min. dipped in absolute 9 6 9 and
7 0 9 alcohol. rinsed in distilled water. placed in absolute
methanol with 3% H Z 0 2for 10 min. and rinsed in distilled
water. Section3 u ere then dipped in citrate buffer. pH 6 and
microwaw-treated at 92°C for 10 min. .4fter cooling at
pS3 and PCNA in inflammatory papillary hyperpkia of palate
I Kaplln cr aJ
I95
room temperature for 10 min. the p r i m q antibody (DO-7,
150) was added for 1 h. This dilution was chosen as it
yielded best staining quality. Sections were then rinsed in
PBS for 10 min, reacted with the biotinilated second anti-
body for 10 min. rinsed in PBS for 10 min. stained with
AEC substrate chromogen. and rinsed in distilled water for
4 min. Nuclear staining with Mayers hematoxylin solution
(Sigma Diagnostics. USA) was followed by slide covering
with glycerol gelatin. As controls. sections were stained
without the primary antibodies.
PCA!1 sraining
The procedures were essentially similar to those described
for p53. except sections were neither heated for dewaxing
nor microwaved, since the antibody was heat-sensitive
according to the manufacturer. As well. slides were placed
in absolute methanol and 0.39 HZO,for 20 min. cobered
by aluminium foil. rinsed in PBS. pH 7.3 for 15 min. placed
in goat serum for 10 min. and reacted with the primary anti-
body tPC-10. 150) for 1 h. This antibody dilution was
chosen again because it yielded the best staining quality.
The remaining stages were identical to those described
for p5i.
Hisrotnorphornetn
Epirhelial widrh All H&E stained samples were examined
at a magnification of x 100. using a standard I 0 0 point g i d .
The epithelial width was measured by examining three
m a s of epithelium at the widest dimension and measuring
i t in each slide. The mean width for the IPHP and control
groups was then calculated.
lnj4ammaron infilrrare densic On the same HBrE stained
slides. the inflammatory infiltrate was identified as chronic.
acute. or mixed and evaluated semi-quantitatively on a
score of 0 to 4 (0 - no inflammation visible; 1 - scattered
inflammatorj cells only; 2 - mild; 3 - moderate: 3 - dense
inflammatory infiltrate). The mean scores for the IPHP and
control groups were calculated.
Anal~sisof p53 and PCN.4 A positive stained cell was
considered only when clear nuclear staining was present.
Positibe stained cells were counted only in the epithelial
layers. The epithelial width was divided into three compart-
ments: basal (basal layer onlq). suprabasal (lower 1/3 of
the spinous layer) and superficial (upper 213 of the spinous
and keratinized layer, if present). At a magnification of
~100. 10 random fields were screened and the number of
positice cells and their location within the compartments
were recorded. The mean number of positive stained cells
w a s calculated for IPHP and control groups. Data were col-
lected independently by two of the authors (IK and MV)
and found comparable.
Statistical analysis was performed using r-test for inde-
pendent samples and Leven's test for equality of variances.
Results
All patients in the study group wore ill-fitting dentures.
 p53 and PCNA in inflammatorypapillary hyperpiask of palate
I Kaplan n a1

I96
Table 2 Histomorphornrtnc andysi\ of immunohi\t,~,c.hrmicnll~!mined
cell for p53 and K N A *

IPHP 3.75? 7.69 21.45 5 19.07

Control 0.8 1 2 2.36 12.47? 1 1 . 5 2
P < 0.001 P < 0.001

"Data _niven in cells per grid field at magnification x-100

Figure 1 Histopathology of IPHP presenting papillary pattern with

pseudo-cpitheliomatous hyperplasia and marked chronic i n f l m a t o n ;
infiltrates (Hematoxylin & Eosin stain. original magnification ~ 1 0 0 )

Culrures for Candida

All cultures from both the palatal mucosa and the denture
base in IPHP patients presented as cream-colored, smooth
or rough convex colonies. This pattern suggested different
Candido species since Sabourand's agar. consisting of peni-
cillin and streptomycin. suppresses most of the commensal
oral bacteria (Silverman er al. 1990). Figure 2 lrnmunostaining of IPHP for p53 presenting numerouh positive
cells in basal and suprabasal area (arrowheads1 (ABC stain with DO-7.
P.4S-stained slides from biopsy and autopsy material original magnification x 100)
Candido organisms were not identified in any of the IPHP
or control cases.
in Table 2. For p53. a three-fold increase in the number of
Gram-stained slides from biopsy and oiiropsy marerial positive cells was evident in IPHP ( P < 0.001 ) (Figure 2 ) .
Microscopy of Gram-stained slides showed neither charac- In the normal palate, only scattered cells were positive for
teristic rounded nor oval budding cells of yeast blastospores p53 (Figure 3). In both normal and IPHP. positive cells
(yeast form) nor the hyphal phase. Small foci of Gram- were located in the basal and suprabasal areas only. A two-
positive organisms were observed in two cases of IPHP that fold increase of PCNA positive cells was seen in IPHP
were interpreted as bacteria according to their small size. when compared to normals ( P < 0.001) (Figures 4 and 5 ) .
All control cases were negative. Positive cells were also located only in the basal and supra-
basal areas in both normal and IPHP (Figures 4 and S).
Histolog? and hisrornorphornetv
Histologic examination of all lesions revealed papillary pro- Discussion
jections covered with parakeratotic stratified squarnous epi-
thelium. The epithelium was hyperplastic and often demon- IPHP is generally considered as an inflammatory reactive
strated pseudoepitheliomatous hyperplasia (Figure 1 ). lesion that is associated with trauma to the mucosa from ill-
There was no evidence of dysplasia. The connective tissue
was well-vascularized and infiltrated by numerous chronic
inflammatory cells.
Table 1 shows the histomorphometric analysis of the epi-
thelial width and inflammation scores. which were signifi-
cantly highcr in IPHP than in controls (P< 0.001).
The results of pS3 and PCNA immunostaining are shown

Table 1 Histomorphornetric analysis of epithelial width and inflamma-

ton cell densiry

Epirhelrul width+ lnjiammotion cell drnsifi

IPHP *
5.11 1.96 1.83 k 0.83
Control 3.15 2 1.28 0.63 f 0.64
P < 0.001 P < 0.001 Figure3 Immunostaining of normal palatal mucosa for p53 showing
only a few scattered positive cells (arrow) in b a d and supmbiLsa1 areas
*Data given in -grid units at magnification xl00 [ABC stain with W-7.original magnification xl001

Figure 1 Immuno>ruinin: 01' IPHP for PCNA bhowinp numerim
positive c r l l r in basal and w p r ~ h d darea!. I 4 B C slain with PC-10.
onginal mapticarion % l O O i
Figure I Irnrnunu.;raining of norm31 palatal mucosa for PCNA showing
rcanered p o d i \ c cell\ i n h a d und suprabasal arm5 (arrowhead\) 4BC
stain uirh PC- 10. on:inal rnagnilicarion x l 0 0 1
fitting dentures and Cclriditlri infection. It does not present
cellular d>splasia nor has it been reported to transform to
malignant?. However. since the lesion could present histo-
logic features of marked h>perplasia. reaching a degree of
pseudoepi theliomataus (pseudocarcinomatous) hyperplasia.
i t is not unusual for general patholopibts who are unfamiliar
rvith oral lesions. to misdiagnose it as a uzll-differentiated
squamou5 cell carcinoma (Bhashar er al. 1970).
The present stud) confirms the relation betueen the
trauma of ill-fitting dentures and Candido infection uith
the appearance of IPHP. .A11 patients bore inadequate
appliances and the microbiological anal>sis confirmed the
presence of Ctiiidith in all cultures taken with swabs from
both the palatal mucosa and denture base. All histologic
sections stained Kith Gram and PAS were negative for
Candidal h>phae. nhich is in agreement with previous
studies (Budtz-Jorgensen. 1970: Bergendal and Isacsson.
1983: W'exott and Correll. 1984).
The histomorphometric analysis in the present stud)
showed that IPHP lesions were associated with a signifi-
cantly increased epithelial width. as bell as with a marked
increase in the inflammatory infiltrate cell density as com-
pared with normal palatal mucosa. Prtvious studies in
which IPHP was e\ aluated semi-quantitatively showed
compxatiLe results t Budti-Jorgensen. 1970: Berpendal and
Isacsson. I983 ).
p53 and PCNA in inflammatory p a p i l l q hyperplasia of palate
1 Kiplan e: 01
I97
In~n~iinohistocheniistryfor pS3 showed a significant
increase in the number of positi1.e cells in the basal and
suprabasal areas in IPHP compared to the normal palate.
For PCN.4. a similar pattern was shuum uith a significant
increased expression in the IPHP group compared to con-
tro1.s. both in basal and suprabasal locations. The interpret-
ation of these findings poses a dilemma. According to s o -
mil studies. ocerexpression of p53 and PCNA. as well as
their suprabasal Icoation. are indicative of malignant poten-
tial (Hall er al. 1990; Ogden er al. 1992; LVarnaliulasuriya
and Johnson, 1997: Kishioha et (11. 1993; Kohayashi er ~ l .
1995: Sugerman er al. 1995). Thus. there is a discrepancy
between the immunohistochemical results and the blunt his-
tological features of this inflammatorj lesion of the palate.
One of the most commonly used antibodies for p53 on
formalin-fixed. paraffin-embedded archival tissues has been
DO-7. It is widely used because of its reliability and avail-
ability. though it can react with both uild type p53 and its
mutated form (Girod p r 01. 1993: Piffio rr al. 1995).The
half life of the uild type p53 protein is short. therefore. its
level in normal cells is below the detection threshold of
the irnmunostaining methods. Overexpression of pi-3 may
reflect high levels of the wild type protein as a response to
DSA damage. Inactivated forms of uild type p53 protein.
either due to its association with viral proteins. such as
HPV-€6. or to inflammatoq cytokines. like TNF-cr and
INF-y. have elongated half lives (Sauter er al, 1991). In
both of these conditions, the DO-7 antibody would detect
the wild type p53. It can be assumed that in the IPHP cases.
the associated marked inflammatorj infiltrate was the rea-
son for the increased level of ps?. most probably of the
wild tjpe configuration. Other inflammatory lesions have
demonstrated a sinular increase level of p53 (Helander ef
al, 1993; Soini et al. 1991). Many of the mutations in the
p53 gene result in an altered protein configuration. which
also tends to accumulate in the cell and yields a positive
reaction with the DO-7 antibody. Although it is known that
the pS-3 gene is mutated in approximately 70% of all adult
solid tumors (Todd er al. 1997).orerexpression of pS3 pro-
tein. as detected by inimunohistochemistry, is not necessar-
ily equivalent uith a mutated p53 gene (Ogden et 01. 1992:
Bongers pr nl. 1995). It has recently been shown that on14
about 50% of oral malignant and premalignant cases that
were positice for p53 by immunostaining had mutations at
the gene lmel (N)lander et 01. 1995; Tavassoli et al. 19971.
The fact that immunohistochemistq can detect higher
than nornial l e ~ e l sof p53 in benign inflammatory lesions.
such as IPHP. as hell as in malignant conditions. suggests
that the intcrpreration of current immunohistochemical
results may necessitate a thorough re-evaluation. This is
supported by Rajrndrakumar er a1 ( 1997) who documented
an increased expression of p53 i n a large number of benign
conditions of the respiratorj tract.
The results of PCNA immunohistochemistq are even
less consistent than those for p53. Although the increased
expression of PCNA. as well as its location in suprabasal
epithelium have been interpreted as indicators of dysplasia
or malignancy (Hall et 01. 1990; Shin et 01. 1993; Huang
et ul. 1991; Kobayashi er al. 1995). the findings of this
stud! indicate that increased expression of PCK.4 in a
s u p r a b a d location can be found in inflammatory non-
 pS3 and PCNA in inflammatory papillary hlptrplasii d palate
I Kaohn cf d
I98
neoplastic lesions. PCNA results are apparently influenced
by the biologic behavior of the protein itself, a long half
life in the range of 8 to 20 h (Isik et al, 1992) and by
laboratory conditions (Hall et ul, 1990). However, the over-
expression of PCNA in IPHP in the present study can be
explained by the presence of Cundida microorganisms at
the epithelial-denture base interface. It is suggested that
both the epithelial hyperplasia and the associated inflam-
mation in IPHP are induced by the effect of Candida and
that the PCNA overexpression accompanies the benign epi-
thelial hyperplasia rather than being a sign of malignant
potential. Thus, it is suggested that PCNA, like p53, is not
a reliable marker of the malignant potential of cells in cases
of epithelial proliferative lesions associated with a marked
inflammatory infiltrate, as is the case of IPHP. This has
been supported by others (Nylander ef al, 1995).
Immunodetection of the widely used p53 and PCNA as
biologic markers for malignant potential is influenced by a
variety of factors. Thus, the interpretation of their
expression by currently available immunohistochemical
methods in lesions associated with an inflammatory reac-
tion should be made with great caution, especially when
using antibodies that are unable to distinguish between the
wild type and mutated forms of the protein products of
oncogenes. Without genetic proof of mutations in genes
involved in the cell cycle, immunohistochemistry alone for
p53 or PCNA is neither specific nor sensitive enough to be
used as an indicator of the potential for malignant trans-
formation.
Acknowledgements
This study was supported by the Ed and Herb Stain Chair in Oral
Pathology. Tel Aviv University. The authors wish to thank Pro-
fessor Yehuda Hiss for contributing the autopsy specimens, Mrs
Nurit Chimovits and Mrs Hanna Vered for their technical assist-
ance in the preparation of the histological material. and Ms Rita
Lazar for editorial assistance.
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